Giustizieri Michela, Bernardi Giorgio, Mercuri Nicola B, Berretta Nicola
Centro Europeo di Ricerca sul Cervello Fondazione Santa Lucia Istituto di Ricovero e Cura a Carattere Scientifico, Via del Fosso di Fiorano, 64, 00143 Rome, Italy.
J Neurophysiol. 2005 Sep;94(3):1992-2003. doi: 10.1152/jn.00171.2005. Epub 2005 Jun 8.
We investigated the mechanisms of presynaptic inhibition of GABAergic neurotransmission by group III metabotropic glutamate receptors (mGluRs) and GABA(B) receptors, in dopamine (DA) neurons of the substantia nigra pars compacta (SNc). Both the group III mGluRs agonist L-(+)-2-amino-4-phosphonobutyric acid (AP4, 100 microM) and the GABA(B) receptor agonist baclofen (10 microM) reversibly depressed the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) to 48.5 +/- 2.7 and 79.3 +/- 1.6% (means +/- SE) of control, respectively. On the contrary, the frequency of action potential-independent miniature IPSCs (mIPSCs), recorded in tetrodotoxin (TTX, 1 microM) and cadmium (100 microM) were insensitive to AP4 but were reduced by baclofen to 49.7 +/- 8.6% of control. When the contribution of voltage-dependent calcium channels (VDCCs) to synaptic transmission was boosted with external barium (1 mM), AP4 became effective in reducing TTX-resistant mIPSCs to 65.4 +/- 3.9% of control, thus confirming a mechanism of presynaptic inhibition involving modulation of VDCCs. Differently from AP4, baclofen inhibited to 58.5 +/- 6.7% of control the frequency mIPSCs recorded in TTX and the calcium ionophore ionomycin (2 microM), which promotes Ca2+-dependent, but VDCC-independent, transmitter release. Moreover, in the presence of alpha-latrotoxin (0.3 nM), to promote a Ca2+-independent vesicular release of GABA, baclofen reduced mIPSC frequency to 48.1 +/- 3.2% of control, while AP4 was ineffective. These results indicate that group III mGluRs depress GABA release to DA neurons of the SNc through inhibition of presynaptic VDCCs, while presynaptic GABA(B) receptors directly impair transmitter exocytosis.
我们研究了黑质致密部（SNc）多巴胺（DA）神经元中III组代谢型谷氨酸受体（mGluRs）和GABA(B)受体对GABA能神经传递的突触前抑制机制。III组mGluRs激动剂L-(+)-2-氨基-4-膦酰丁酸（AP4，100微摩尔）和GABA(B)受体激动剂巴氯芬（10微摩尔）均可使自发性抑制性突触后电流（sIPSCs）频率分别可逆性降低至对照值的48.5±2.7%和79.3±1.6%（均值±标准误）。相反，在河豚毒素（TTX，1微摩尔）和镉（100微摩尔）存在下记录的与动作电位无关的微小抑制性突触后电流（mIPSCs）频率对AP4不敏感，但被巴氯芬降低至对照值的49.7±8.6%。当用外部钡（1毫摩尔）增强电压依赖性钙通道（VDCCs）对突触传递的作用时，AP4可有效将TTX抗性mIPSCs降低至对照值的65.4±3.9%，从而证实了一种涉及VDCCs调节的突触前抑制机制。与AP4不同，巴氯芬将在TTX和钙离子载体离子霉素（2微摩尔）存在下记录的mIPSCs频率抑制至对照值的58.5±6.7%，离子霉素可促进钙离子依赖性但与VDCC无关的递质释放。此外，在存在α-银环蛇毒素（0.3纳摩尔）以促进GABA的非钙离子依赖性囊泡释放时，巴氯芬将mIPSC频率降低至对照值的48.1±3.2%，而AP4无效。这些结果表明，III组mGluRs通过抑制突触前VDCCs降低向SNc的DA神经元释放GABA，而突触前GABA(B)受体直接损害递质的胞吐作用。
